Vascular cognitive impairment (VCI) is a major cause of intellectual loss in the elderly. Subcortical ischemic vascular disease (SIVD) is a progressive form of VCI due to small vessel disease associated with white matter hyperintensities (WMHs) on MRI. Damage to the white matter has been attributed to hypoxic hypoperfusion, which induces an inflammatory cascade. Disruption of the blood-brain barrier (BBB) by matrix metalloproteinases (MMPs) occurs as part of a neuroinflammatory response. During the prior grant, we identified multiple biomarkers associated with white matter pathophysiology: proton magnetic resonance spectroscopy (1H-MRS) which shows reduced N-acetylaspartate (NAA) in regions of injured white matter;increased BBB permeability measured by dynamic contrast-enhanced MRI (DCEMRI) and albumin index;and reduced MMP-2 index derived from CSF and blood. An unexpected finding was that patients with SIVD and large white matter lesions had reduced levels of CSF amyloid A&#946;1-42 without an increase in total- or phospho-tau. The hypotheses of this proposal are that growth of the WMHs are due to disruption of the BBB and neuroinflammation associated with MMPs, that patients with both Alzheimer[unreadable]s disease (AD) and VCI (Mixed) have biomarkers for both diseases, and that multimodal biomarkers validated by long-term follow-up can identify the patients with SIVD at onset of the illness. Specific aim 1 will correlate growth of WMHs with disruption of the BBB and neuroinflammation. We plan to recruit 70 patients with VCI, 30 with AD and 20 controls. Patients will have MR measurements of NAA and BBB permeability with MRI at entry and after one and two years. CSF will be collected to measure MMP indexes and albumin index. Growth of WMHs after one and two years will be determined by NAA and lesion size on MRI. Correlation of rate of growth will be done statistically with BBB permeability and MMP levels. Specific aim 2 will identify the presence of vascular disease of the white matter in patients with suspected AD as identified by biomarkers for AD. We plan to recruit 30 patients with AD and WMHs to determine the overlap between SIVD and AD. Vascular disease of the white matter will be determined by reduced NAA and increased BBB permeability in white matter. This aim will identify Mixed patients. Specific aim 3 will determine a set of biomarkers that can be measured in the early stages of VCI and are predictive of progressive deterioration of patients. Diagnoses will be made clinically after long-term follow-up independent of the biomarkers. The significance is that VCI is increasing as the population ages and that mixed VCI/AD are commonly found at autopsy. Our studies will provide a set of multimodal biomarkers that can be used to identify patients early in the course of SIVD when treatment would be most effective.